Varenicline, 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine, is known to bind to neuronal nicotinic acetylcholine specific receptor sites and is useful in modulating cholinergic function. This compound is useful in the treatment of inflammatory bowel disease, irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, vasoconstriction, anxiety, panic disorder, depression, cognitive dysfunction, drug/toxin-induced cognitive impairment (e.g., from alcohol, barbiturates, vitamin deficiencies, recreational drugs, lead, arsenic, mercury), particularly, nicotine dependency, addiction and withdrawal; including use in smoking cessation therapy. Varenicline is represented by the following structural formula:
and its first synthesis was disclosed in U.S. Pat. No. 6,410,550 (hereinafter referred to as the '550 patent). Varenicline is sold by Pfizer under the brand name CHANTIX™ to help adults quit smoking by blocking α4β2 nicotinic acetylcholine receptor subtypes. It is orally administered as tablets containing 0.85 mg or 1.71 mg of varenicline tartrate equivalent to 0.5 mg or 1 mg of varenicline.
The '550 patent describes various processes for the preparation of aryl fused azapolycyclic compounds, including varenicline, and their pharmaceutically acceptable salts, combinations with other therapeutic agents, and methods of using such combinations in the treatment of neurogical and psychological disorders. Varenicline has been exemplified as a free base and a hydrochloride salt in the '550 patent.
U.S. Pat. No. 6,890,927 (hereinafter referred to as the '927 patent) discloses tartrate salts, including L-tartrate, D-tartrate, D,L-tartrate and meso-tartrate, of varenicline and their polymorphs, processes for their preparation, and pharmaceutical compositions thereof. The '927 patent further discloses various polymorphs of the varenicline L-tartrate salt, including two anhydrous polymorphs (Forms A & B) and a hydrate polymorph (Form C), and characterizes them by powder X-ray diffraction (P-XRD), X-ray crystal structure, solid state 13C NMR spectroscopy, and Differential Scanning calorimetry (DSC).
Varenicline tartrate, 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine, (2R,3R)-2,3-dihydroxybutanedioate (1:1), has a molecular weight of 361.35 Daltons, and a molecular formula of C13H13N3.C4H6O6. Varenicline tartrate is represented by the following structural formula:

U.S. Pat. Nos. 6,897,310 and 6,951,938 describe a process for the preparation of aryl fused azapolycyclic compounds and their pharmaceutically acceptable salts in combination with another therapeutic agents and methods of using such combinations in the treatment of neurogical and psychological disorder. The '938 patent discloses the ring closure for making quinoxalines by reacting diamine compound with glyoxal or glyoxal derivatives in water or other polar solvents such as tetrahydrofuran, dimethylformamide or dimethylsulfoxide at a temperature of about 40° C. to about 100° C.
PCT publication WO2004/108725 describes a process for the preparation of substituted quinoxalines by cyclization of the corresponding diamine compound with 2,3-dihydroxy-1,4-dioxane.
PCT Publication WO 2008/060487 (hereinafter referred to as the '487 application) discloses crystal forms of intermediates used in the process for the preparation of varenicline tartrate including the varenicline free base. According to the '487 application, the varenicline free base exists in four crystalline forms (Form A, Form C, Form D and Form E).
The synthetic routes described in the above mentioned prior art suffers from disadvantages such as high cost of reagents, the use of pyrophoric and hazardous reagents, the use of additional reagents and low yields of product. Hence, these routes are not advisable for scale up operations.
A need remains for an improved and commercially viable process of preparing a substantially pure varenicline or a pharmaceutically acceptable salt thereof, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation, in a shorter reaction time. Desirable process properties include less hazardous and environmentally friendly reagents, reduced cost, greater simplicity, increased product purity and increased yield of the product.